Autonomic nervous system control via high frequency spinal cord modulation, and associated systems and methods

ABSTRACT

Autonomic nervous system control via high frequency spinal cord modulation, and associated systems and methods. A method for treating a patient in accordance with a particular embodiment includes selecting a neural modulation site to include a neural population of the patient&#39;s spinal cord, and selecting parameters of a neural modulation signal to at least reduce an autonomic system deficit in the patient.

CROSS-REFERENCE TO RELATED APPLICATION

The present application is a continuation of U.S. patent applicationSer. No. 13/922,765, filed Jun. 20, 2013, which claims priority to U.S.Provisional Application No. 61/663,466, filed on Jun. 22, 2012, and areincorporated herein by reference. To the extent the foregoingapplication and/or any other materials incorporated herein by referenceconflict with the present disclosure, the present disclosure controls.

TECHNICAL FIELD

The present technology is directed generally to autonomic nervous systemcontrol obtained via high frequency spinal cord modulation, andassociated systems and methods.

BACKGROUND

Neurological stimulators have been developed to treat pain, movementdisorders, functional disorders, spasticity, cancer, cardiac disorders,and various other medical conditions. Implantable neurologicalstimulation systems generally have an implantable pulse generator andone or more leads that deliver electrical pulses to neurological tissueor muscle tissue. For example, several neurological stimulation systemsfor spinal cord stimulation (SCS) have cylindrical leads that include alead body with a circular cross-sectional shape and one or moreconductive rings spaced apart from each other at the distal end of thelead body. The conductive rings operate as individual electrodes and, inmany cases, the SCS leads are implanted percutaneously through a largeneedle inserted into the epidural space, with or without the assistanceof a stylet.

While the foregoing stimulators and techniques have proven beneficial inmany instances, there remains a significant need in the medicalcommunity for improved devices and therapies that can address a broadrange of patient indications.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a partially schematic illustration of an implantable spinalcord modulation system positioned at the spine to deliver therapeuticsignals in accordance with several embodiments of the presentdisclosure.

FIG. 1B is a partially schematic, cross-sectional illustration of apatient's spine, illustrating representative locations for implantedlead bodies in accordance with embodiments of the disclosure.

FIG. 2A is a graph illustrating representative patient VAS scores as afunction of time for multiple patients receiving therapy in accordancewith embodiments of the disclosure.

FIG. 2B is a graph illustrating normalized pain scores for the patientsidentified in FIG. 2A, during an initial post-trial period.

FIG. 3 is a partially schematic, isometric illustration of an animalspinal cord segment and associated nerve structures, used to demonstratetechniques in accordance with the present disclosure.

FIG. 4 is a graph illustrating stimulus and response characteristics asa function of time for an animal receiving noxious electricalstimulation in accordance with an embodiment of the disclosure.

FIGS. 5A-5E illustrate response data for an animal receiving noxiouselectrical stimulation and therapy in accordance with an embodiment ofthe disclosure.

FIGS. 6A-6F illustrate animal response data for animals receivingnoxious pinch stimuli in accordance with another embodiment of thedisclosure.

FIG. 7A is a graphical illustration comparing modulation amplitudeeffects for standard SCS with those for the presently disclosedtechnology.

FIG. 7B is a graph of amplitude as a function of frequency, illustratingdifferent therapeutic and non-therapeutic regimes.

FIG. 8 is a table illustrating representative effects of the autonomicnervous system on representative organs.

DETAILED DESCRIPTION 1.0 Introduction

The present technology is directed generally to spinal cord modulationand associated systems and methods for controlling the autonomic nervoussystem and/or otherwise affecting the autonomic nervous system (ANS) viawaveforms with high frequency elements or components (e.g., portionshaving high fundamental frequencies). These frequencies have also beendemonstrated to provide pain relief generally with reduced or eliminatedside effects. Such side effects can include unwanted motor stimulationor blocking, and/or interference with sensory functions other than thetargeted pain, and/or patient proprioception. Several embodimentscontinue to provide pain relief for at least some period of time afterthe spinal cord modulation signals have ceased. Specific details ofcertain embodiments of the disclosure are described below with referenceto methods for modulating one or more target neural populations (e.g.,nerves) or sites of a patient, and associated implantable structures forproviding the modulation. The following sections also describephysiological mechanisms by which it is expected that methods inaccordance with certain embodiments achieve the observed results. Someembodiments can have configurations, components or procedures differentthan those described in this section, and other embodiments mayeliminate particular components or procedures. A person of ordinaryskill in the relevant art, therefore, will understand that thedisclosure may include other embodiments with additional elements,and/or may include other embodiments without several of the featuresshown and described below with reference to FIGS. 1A-8.

In general terms, aspects of many of the following embodiments aredirected to producing a therapeutic effect that includes pain reductionand/or ANS control in the patient. The therapeutic effect can beproduced by inhibiting, suppressing, downregulating, blocking,preventing, or otherwise modulating the activity of the affected neuralpopulation. In many embodiments of the presently disclosed techniques,therapy-induced paresthesia is not a prerequisite to achieving painreduction, unlike standard SCS techniques. It is also expected that thetechniques described below with reference to FIGS. 1A-8 can producelonger lasting results than can existing spinal cord stimulationtherapies. In particular, these techniques can produce results thatpersist after the modulation signal ceases. Accordingly, thesetechniques can use less power than existing techniques because they neednot require delivering modulation signals continuously to obtain abeneficial effect.

In particular embodiments, therapeutic modulation signals are directedgenerally to the patient's spinal cord, e.g., the dorsal column of thepatient's spinal cord. In other embodiments, the modulation signals canbe directed to other neural populations, including but not limited tothe dorsal horn, dorsal root, dorsal root ganglion, dorsal root entryzone, and/or other particular areas at or in close proximity to thespinal cord itself. The foregoing areas are referred to hereincollectively as the spinal cord region. In still further embodiments,the modulation signals may be directed to other neurological structuresand/or target neural populations.

Several aspects of the technology are embodied in computing devices,e.g., programmed/programmable pulse generators, controllers and/or otherdevices. The computing devices on which the described technology can beimplemented may include one or more central processing units, memory,input devices (e.g., input ports), output devices (e.g., displaydevices), storage devices, and network devices (e.g., networkinterfaces). The memory and storage devices are computer-readable mediathat may store instructions that implement the technology. In manyembodiments, the computer readable media are tangible media. In otherembodiments, the data structures and message structures may be stored ortransmitted via an intangible data transmission medium, such as a signalon a communications link. Various suitable communications links may beused, including but not limited to a local area network and/or awide-area network.

2.0 Overall System Characteristics

FIG. 1A schematically illustrates a representative patient system 100for providing relief from chronic pain and/or other conditions, and/oraffect the ANS, arranged relative to the general anatomy of a patient'sspinal cord 191. The overall patient system 100 can include a signaldelivery system 110, which may be implanted within a patient 190,typically at or near the patient's midline 189, and coupled to a pulsegenerator 121. The signal delivery system 110 can provide therapeuticelectrical signals to the patient during operation. In a representativeexample, the signal delivery system 110 includes a signal deliverydevice 111 that carries features for delivering therapy to the patient190 after implantation. The pulse generator 121 can be connecteddirectly to the signal delivery device 111, or it can be coupled to thesignal delivery device 111 via a signal link 113 (e.g., an extension).In a further representative embodiment, the signal delivery device 111can include an elongated lead or lead body 112. As used herein, theterms “lead” and “lead body” include any of a number of suitablesubstrates and/or support members that carry devices for providingtherapy signals to the patient 190. For example, the lead 112 caninclude one or more electrodes or electrical contacts that directelectrical signals into the patient's tissue, such as to provide forpatient relief. In other embodiments, the signal delivery device 111 caninclude structures other than a lead body (e.g., a paddle) that alsodirect electrical signals and/or other types of signals to the patient190.

The pulse generator 121 can transmit signals (e.g., electrical signals)to the signal delivery device 111 that up-regulate (e.g., stimulate orexcite) and/or down-regulate (e.g., block or suppress) target nerves. Asused herein, and unless otherwise noted, the terms “modulate” and“modulation” refer generally to signals that have either type of theforegoing effects on the target nerves. The pulse generator 121 caninclude a machine-readable (e.g., computer-readable) medium containinginstructions for generating and transmitting suitable therapy signals.The pulse generator 121 and/or other elements of the system 100 caninclude one or more processors 122, memories 123 and/or input/outputdevices. Accordingly, the process of providing modulation signals,providing guidance information for locating the signal delivery device111, and/or executing other associated functions can be performed bycomputer-executable instructions contained by computer-readable medialocated at the pulse generator 121 and/or other system components. Thepulse generator 121 can include multiple portions, elements, and/orsubsystems (e.g., for directing signals in accordance with multiplesignal delivery parameters), carried in a single housing, as shown inFIG. 1A, or in multiple housings.

In some embodiments, the pulse generator 121 can obtain power togenerate the therapy signals from an external power source 118. Theexternal power source 118 can transmit power to the implanted pulsegenerator 121 using electromagnetic induction (e.g., RF signals). Forexample, the external power source 118 can include an external coil 119that communicates with a corresponding internal coil (not shown) withinthe implantable pulse generator 121. The external power source 118 canbe portable for ease of use.

During at least some procedures, an external programmer 120 (e.g., atrial modulator) can be coupled to the signal delivery device 111 duringan initial procedure, prior to implanting the pulse generator 121. Forexample, a practitioner (e.g., a physician and/or a companyrepresentative) can use the external programmer 120 to vary themodulation parameters provided to the signal delivery device 111 in realtime, and select optimal or particularly efficacious parameters. Theseparameters can include the location from which the electrical signalsare emitted, as well as the characteristics of the electrical signalsprovided to the signal delivery device 111. In a typical process, thepractitioner uses a cable assembly 114 to temporarily connect theexternal programmer 120 to the signal delivery device 111. Thepractitioner can test the efficacy of the signal delivery device 111 inan initial position. The practitioner can then disconnect the cableassembly 114 (e.g., at a connector 117), reposition the signal deliverydevice 111, and reapply the electrical modulation. This process can beperformed iteratively until the practitioner obtains the desiredposition for the signal delivery device 111. Optionally, thepractitioner may move the partially implanted signal delivery element111 without disconnecting the cable assembly 114.

After a trial period with the external programmer 120, the practitionercan implant the implantable pulse generator 121 within the patient 190for longer term treatment. The signal delivery parameters provided bythe pulse generator 121 can still be updated after the pulse generator121 is implanted, via a wireless physician's programmer 125 (e.g., aphysician's remote) and/or a wireless patient programmer 124 (e.g., apatient remote). Generally, the patient 190 has control over fewerparameters than does the practitioner.

FIG. 1B is a cross-sectional illustration of the spinal cord 191 and anadjacent vertebra 195 (based generally on information from Crossman andNeary, “Neuroanatomy,” 1995 (published by Churchill Livingstone)), alongwith multiple signal delivery devices 111 (shown as signal deliverydevices 111 a-111 d) implanted at representative locations. For purposesof illustration, multiple signal delivery devices 111 are shown in FIG.1B implanted in a single patient. In actual use, any given patient willlikely receive fewer than all the signal delivery devices 111 shown inFIG. 1B.

The spinal cord 191 is situated within a vertebral foramen 188, betweena ventrally located ventral body 196 and a dorsally located transverseprocess 198 and spinous process 197. Arrows V and D identify the ventraland dorsal directions, respectively. The spinal cord 191 itself islocated within the dura mater 199, which also surrounds portions of thenerves exiting the spinal cord 191, including the ventral roots 192,dorsal roots 193 and dorsal root ganglia 194. The dorsal roots 193 enterthe spinal cord 191 at the dorsal root entry zone 187, and communicatewith dorsal horn neurons located at the dorsal horn 186. In oneembodiment, a single first signal delivery device 111 a is positionedwithin the vertebral foramen 188, at or approximately at the spinal cordmidline 189. In another embodiment, two second signal delivery devices111 b are positioned just off the spinal cord midline 189 (e.g., about 1mm. offset) in opposing lateral directions so that the two signaldelivery devices 111 b are spaced apart from each other by about 2 mm.In still further embodiments, a single signal delivery device or pairsof signal delivery devices can be positioned at other locations, e.g.,toward the outer edge of the dorsal root entry zone 187 as shown by athird signal delivery device 111 c, or at the dorsal root ganglia 194,as shown by a fourth signal delivery device 111 d. As will be describedin further detail later, it is believed that high frequency modulationat or near the dorsal root entry zone 187, and/or at or near the dorsalhorn 186 can produce effective patient pain relief, without paresthesia,without adverse sensory or motor effects, and in a manner that persistsafter the modulation ceases.

3.0 Addressing Patient Pain

Systems and methods for treating pain as discussed immediately below,and embodiments for addressing other patient indications via theautonomic nervous system are described later under Section 4.0. Asdiscussed below, the pain may be addressed by applying high frequencymodulation signals to dorsal neural populations. In particularembodiments, it is believed that such modulation signals may affect thewide dynamic range (WDR) neurons. Accordingly, it is further believed(and discussed in Section 4.0) that the modulation signals can affectthe patient's autonomic nervous system, in addition to or in lieu ofaddressing patient pain.

3.1 Representative Results from Human Studies

Nevro Corporation, the assignee of the present application, hasconducted several in-human clinical studies during which multiplepatients were treated with the techniques, systems and devices that aredisclosed herein. Nevro also commissioned animal studies focusing onmechanisms of action for the newly developed techniques. The humanclinical studies are described immediately below and the animal studiesare discussed thereafter.

FIG. 2A is a graph illustrating results from patients who receivedtherapy in accordance with the presently disclosed technology to treatchronic low back pain. In general, the therapy included high-frequencymodulation at the patient's spinal cord, typically between vertebrallevels T9 and T12 (inclusive), at an average location of mid T-10. Themodulation signals were applied at a frequency of about 10 kHz, and atcurrent amplitudes of from about 2.5 mA to about 3 mA. Pulse widths wereabout 35 μsec., at 100% duty cycle. Further details of representativemodulation parameters are included in U.S. Pat. No. 8,170,675incorporated herein by reference.

The graph shown in FIG. 2A illustrates visual analog scale (“VAS”)scores for seven representative patients as a function of time during aclinical study. Individual lines for each patient are indicated withcircled numbers in FIG. 2A, and the average is indicated by the circledletter “A”. The VAS pain scale ranges from zero (corresponding to nosensed pain) to 10 (corresponding to unbearable pain). At the far leftof FIG. 2A are VAS scores taken at a baseline point in time 145,corresponding to the patients' pain levels before receiving any highfrequency modulation therapy. During a trial period 140, the patientsreceived a high frequency modulation therapy in accordance with theforegoing parameters and the patients' VAS scores dropped significantlyup to an end of trial point 146. In addition, many patients readilyreduced or eliminated their intake of pain medications, despite thenarcotic characteristics of these medications. During an initialpost-trial period 141 (lasting, in this case, four days), the patients'VAS scores increased on average after the high frequency modulationtherapy has been halted. The rate at which pain returned after the endof the trial period varied among patients, however, as will be discussedin further detail later. Following the four-day initial post-trialperiod 141 was an interim period 142 that lasted from about 45 days toabout 80 days (depending on the patient), with the average being about62 days. After the interim period 142, a four-day pre-IPG period 143commenced ending at an IPG point 144. At the IPG point 144, the patientswere implanted with an implantable pulse generator 121, generallysimilar to that described above with reference to FIG. 1A.

The VAS scores recorded at the baseline 145 and the end of the trial 146were obtained by the patients recording their levels of pain directly tothe practitioner. During the initial post-trial period 141 and thepre-IPG period 143, the patients tracked their VAS score in patientdiaries.

FIG. 2B illustrates data in the initial post-trial period 141 describedabove with reference to FIG. 2A. For each patient, the pain levelsreported in FIG. 2A as VAS scores are shown in FIG. 2B as normalized byevaluating the patient's pain level at the end of trial 146 and at theIPG point 144. Accordingly, for each patient, the normalized pain valueis zero at the end of trial 146, and 100% at the IPG point 144. As shownin FIG. 2B, the patients generally fell into two categories: a firstgroup for whom the pain scores rapidly rose from 0% to nearly 100%within a span of about one day after the end of trial 146 (representedby lines 1, 2, 3 and 5); and a second group for whom the pain increasewas more gradual, spanning several days before reaching levels above 50%(represented by lines 4, 6 and 7). Accordingly, the data indicate thatthe patients' pain levels increased compared to the levels obtained atthe end of trial 146; however, different patients re-developed pain atdifferent rates. The resolution of the data shown in FIG. 2B is not fineenough to identify precisely how long it took for the patients in thefirst group to feel a recurrence of high pain levels. However, it wasobserved by those conducting the studies that the return of the pain forall seven patients was more gradual than is typically associated withstandard SCS methodologies. In particular, practitioners havingexperience with both standard SCS and the presently disclosed technologyobserved that patients receiving SCS immediately (e.g., withinmilliseconds) experience a return of pain upon halting the SCStreatment, while the return of pain for patients receiving the presentlydisclosed therapy was more gradual. Accordingly, it is expected that thepersistence effect of the presently disclosed therapy after beingadministered for two weeks, is likely to be on the order of minutes orhours and, (for many patients), less than one day. It is also believedthat the persistence effect may depend at least in part on how long thetherapy was applied before it was halted. That is, it is expected that,within a given time period, the longer the patient receives thepresently disclosed therapy, the longer the beneficial effect lastsafter the therapy signals are halted. Accordingly, it is expected thatthe presently disclosed therapy can produce effects lasting at least onetenth of one second, at least one second, at least one minute, at leastone hour, and/or at least one day, unlike standard SCS techniques, whichtypically produce effects lasting only milliseconds after the electricalsignal ceases. In still further embodiments, it is expected that atleast some of the lasting effect described above can be obtained byreducing the intensity (e.g., the current amplitude) of the therapysignal, without ceasing the signal altogether. In at least someembodiments (whether the signal intensity is reduced to zero or to anon-zero value), it is expected that a long enough modulation period canproduce a neuroplastic or other change that can last indefinitely, topermanently reduce or eliminate patient pain.

An expected benefit of the persistence or long term effect describedabove is that it can reduce the need to deliver the therapy signalscontinuously. Instead, the signals can be delivered intermittentlywithout significantly affecting pain relief. This arrangement can reducepower consumption, thus extending the life of an implanted battery orother power system. It is expected that the power can be cycledaccording to schedules other than the one explicitly shown in FIGS. 2Aand 2B (e.g., other than two weeks on and up to one day off before asignificant pain recurrence). The following discussion describesexpected potential mechanisms of action by which the presently disclosedtherapy operates, including expected mechanisms by which the presentlydisclosed therapy produces effects persisting after electricalmodulation signals have ceased.

3.2 Representative Results from Animal Studies

FIG. 3 is a partially schematic, isometric view of a portion of ananimal spinal cord 391 illustrative of a study that was performed on arat model to illustrate the principles described herein. Accordingly, inthis particular embodiment, the illustrated spinal cord 391 is that of arat. During this study, a noxious electrical stimulation 370 was appliedto the rat's hind paw 384. Afferent pain signals triggered by thenoxious stimulation 370 traveled along a peripheral nerve 385 to thedorsal root ganglion 394 and then to the dorsal root 393 at the L5vertebral level. The dorsal root 393 joins the spinal cord 391 at thedorsal root entry zone 387, and transmits afferent signals to a dorsalhorn neuron 383 located at the dorsal horn 386. The dorsal horn neuron383 includes a wide dynamic range (“WDR”) cell. An extracellularmicroelectrode 371 recorded signals transmitted by the dorsal hornneuron 383 to the rat's brain, in response to the noxious stimulation370 received at the hind paw 384. A therapeutic modulation signal wasapplied at the dorsal root entry zone 387, proximate to the dorsal horn386.

FIG. 4 is a graph illustrating neural signal amplitude as a function oftime, measured by the recording electrode 371 described above withreference to FIG. 3. FIG. 4 identifies the noxious stimulation 370itself, the dorsal horn neuron's response to A-fiber inputs 372, and thedorsal horn neuron's response to C-fiber inputs 373. The larger A-fiberstrigger an earlier response at the dorsal horn neuron than do thesmaller C-fibers. Both responses are triggered by the same noxiousstimulus 370. The rat's pain response is indicated by downward amplitudespikes. The foregoing response is a typical response to a noxiousstimulus, absent pain modulation therapy.

FIGS. 5A-5E illustrate the dorsal horn neuron response to ongoingnoxious stimuli as the applied therapy signal was altered. The signalapplied to each rat was applied at a constant frequency, which variedfrom rat to rat over a range of from about 3 kHz to about 100 kHz. Theresponse data (which were obtained from nine rats) were relativelyinsensitive to frequency over this range. During the course of thisstudy, the noxious stimuli were provided repeatedly at a constant rateof one stimulus per second over an approximately five-minute period. Atthe outset of the five-minute period, the therapy signal was turned off,resulting in a baseline response 574 a shown in FIG. 5A, and thengradually increased as shown in FIG. 5B, to a maximum intensity shown inFIG. 5C. During the period shown in FIG. 5D, the intensity of thetherapy signal was reduced, and in FIG. 5E, the therapy signal wasturned off. Consistent with the data shown in FIG. 4, the rat's painresponse is indicated by downward spikes. The baseline response 574 ahas a relatively large number of spikes, and the number of spikes beginsto reduce as the intensity of the modulation signal is increased (seeresponse 574 b in FIG. 5B). At the maximum therapy signal intensity, thenumber of spikes has been reduced to nearly zero as indicated byresponse 574 c in FIG. 5C. As the therapy signal intensity is thenreduced, the spikes begin to return (see response 574 d, FIG. 5D), andwhen the modulation signal is turned off, the spikes continue to return(see response 574 e, FIG. 5E). Significantly, the number of spikes shownin FIG. 5E (10-20 seconds after the therapy has been turned off) is notas great as the number of spikes generated in the baseline response 574a shown in FIG. 5A. These data are accordingly consistent with the humantrial data described above with reference to FIGS. 2A and 2B, whichindicated a beneficial effect lasting beyond the cessation of thetherapy signal. These data also differ significantly from resultsobtained from similar studies conducted with standard SCS. Notably,dorsal horn recordings during standard SCS treatments do not indicate areduction in amplitude spikes.

FIGS. 6A-6F illustrate animal response data in a rat model to adifferent noxious stimulus; in particular, a pinch stimulus 670. Thepinch stimulus is a mechanical pinch (rather than an electricalstimulus) at the rat's hindpaw. In each succeeding figure in the seriesof FIGS. 6A-6F, the amplitude of the therapy signal was increased. Thelevels to which the signal amplitude was increased were significantlyhigher than for the human study simply due to a cruder (e.g., lessefficient) coupling between the signal delivery electrode and the targetneural population. The vertical axis of each Figure indicates the numberof spikes (e.g., the spike-shaped inputs 372, 373 shown in FIG. 3) perbin; that is, the number of spikes occurring during a given time period.In the particular embodiment shown in FIGS. 6A-6F, each bin has aduration of 0.2 second, so that there are a total of five bins persecond, or 10 bins during each two-second period. The pinch stimulus 670lasts for three to five seconds in each of FIGS. 6A-6F. In FIG. 6A, thebaseline response 674 a indicates a large number of spikes per binextending over the duration of the pinch stimulus 670. As shown in FIGS.6B-6F, the number of spikes per bin decreases, as indicated by responses674 b-674 f, respectively. In the final Figure in this series (FIG. 6F),the response 674 f is insignificant or nearly insignificant whencompared with the baseline response 674 a shown in FIG. 6A.

The foregoing rat data was confirmed in a subsequent study using a largeanimal model (goat). Based on these data, it is clear that therapysignals in accordance with the present technology reduce pain; further,that they do so in a manner consistent with that observed during thehuman studies.

Returning now to FIG. 3, it is expected (without being bound by theory)that the therapy signals act to reduce pain via one or both of twomechanisms: (1) by reducing neural transmissions entering the spinalcord at the dorsal root 393 and/or the dorsal root entry zone 387,and/or (2) by reducing neural activity at the dorsal horn 386 itself. Itis further expected that the therapy signals described in the context ofthe rat model shown in FIG. 3 operate in a similar manner on thecorresponding structures of the human anatomy, e.g., those shown in FIG.1B. In particular, it is generally known that chronic pain patients maybe in a state of prolonged sensory sensitization at both the nociceptiveafferent neurons (e.g., the peripheral nerve 385 and the associateddorsal root 393) and at higher order neural systems (e.g., the dorsalhorn neuron 383). It is also known that the dorsal horn neurons 383(e.g., the WDR cells) are sensitized in chronic pain states. The noxiousstimuli applied during the animal studies can result in an acute“windup” of the WDR cells (e.g., to a hyperactive state). In accordancewith mechanism (1) above, it is believed that the therapy signalsapplied using the current technology operate to reduce pain by reducing,suppressing, and/or attenuating the afferent nociceptive inputsdelivered to the WDR cells 383, as it is expected that these inputs,unless attenuated, can be responsible for the sensitized state of theWDR cells 383. In accordance with mechanism (2) above, it is expectedthat the presently disclosed therapy can act directly on the WDR cells383 to desensitize these cells. In particular, the patients selected toreceive the therapy described above with reference to FIGS. 2A-2Bincluded patients whose pain was not correlated with peripheral stimuli.In other words, these patients had hypersensitive WDR cells 383independent of whether signals were transmitted to the WDR cells 383 viaperipheral nerve inputs or not. These patients, along with the othertreated patients, experienced the significant pain reductions describedabove. Accordingly, it is believed that the disclosed therapy canoperate directly on the WDR cells 383 to reduce the activity level ofhyperactive WDR cells 383, and/or can reduce incoming afferent signalsfrom the peripheral nerve 385 and dorsal root 393. It is furtherbelieved that the effect of the presently disclosed therapy onperipheral inputs may produce short term pain relief, and the effect onthe WDR cells may produce longer term pain relief. Whether the reducedoutput of the WDR cells results from mechanism (1), mechanism (2), orboth, it is further expected that the high frequency characteristics ofthe therapeutic signals produce the observed results. In addition,embodiments of the presently disclosed therapy produce pain reductionwithout the side effects generally associated with standard SCS, asdiscussed further in U.S. Pat. No. 8,170,675, previously incorporatedherein by reference. These and other advantages associated withembodiments of the presently disclosed technology are described furtherbelow.

Certain of the foregoing embodiments can produce one or more of avariety of advantages, for the patient and/or the practitioner, whencompared with standard SCS therapies. Some of these benefits weredescribed above. For example, the patient can receive beneficial effectsfrom the modulation therapy after the modulation signal has ceased. Inaddition, the patient can receive effective pain relief withoutsimultaneous paresthesia, without simultaneous patient-detectabledisruptions to normal sensory signals along the spinal cord, and/orwithout simultaneous patient-detectable disruptions to normal motorsignals along the spinal cord. In particular embodiments, while thetherapy may create some effect on normal motor and/or sensory signals,the effect is below a level that the patient can reliably detectintrinsically, e.g., without the aid of external assistance viainstruments or other devices. Accordingly, the patient's levels of motorsignaling and other sensory signaling (other than signaling associatedwith the target pain) can be maintained at pre-treatment levels. Forexample, the patient can experience a significant pain reduction that islargely independent of the patient's movement and position. Inparticular, the patient can assume a variety of positions and/orundertake a variety of movements associated with activities of dailyliving and/or other activities, without the need to adjust theparameters in accordance with which the therapy is applied to thepatient (e.g., the signal amplitude). This result can greatly simplifythe patient's life and reduce the effort required by the patient toexperience pain relief while engaging in a variety of activities. Thisresult can also provide an improved lifestyle for patients whoexperience pain during sleep.

Even for patients who receive a therapeutic benefit from changes insignal amplitude, the foregoing therapy can provide advantages. Forexample, such patients can choose from a limited number of programs(e.g., two or three) each with a different amplitude and/or other signaldelivery parameter, to address some or all of the patient's pain. In onesuch example, the patient activates one program before sleeping andanother after waking. In another such example, the patient activates oneprogram before sleeping, a second program after waking, and a thirdprogram before engaging in particular activities that would otherwisecause pain. This reduced set of patient options can greatly simplify thepatient's ability to easily manage pain, without reducing (and in fact,increasing) the circumstances under which the therapy effectivelyaddresses pain. In any embodiments that include multiple programs, thepatient's workload can be further reduced by automatically detecting achange in patient circumstance, and automatically identifying anddelivering the appropriate therapy regimen. Additional details of suchtechniques and associated systems are disclosed in co-pending U.S.application Ser. No. 12/703,683, incorporated herein by reference.

Another benefit observed during clinical studies is that when thepatient does experience a change in the therapy level, it is a gradualchange. This is unlike typical changes associated with conventional SCStherapies. With conventional SCS therapies (e.g., neuromodulationtherapies where electrical stimulation is provided between 2-1,200 Hz,and wherein paresthesia is used to mask a patient's sensation of pain),if a patient changes position and/or changes an amplitude setting, thepatient can experience a sudden onset of pain, often described bypatients as unbearable. By contrast, patients in the clinical studiesdescribed above, when treated with the presently disclosed therapy,reported a gradual onset of pain when signal amplitude was increasedbeyond a threshold level, and/or when the patient changed position, withthe pain described as gradually becoming uncomfortable. One patientdescribed a sensation akin to a cramp coming on, but never fullydeveloping. This significant difference in patient response to changesin signal delivery parameters can allow the patient to more freelychange signal delivery parameters and/or posture when desired, withoutfear of creating an immediately painful effect.

Another observation from the clinical studies described above is thatthe amplitude “window” between the onset of effective therapy and theonset of pain or discomfort is relatively broad, and in particular,broader than it is for standard SCS treatment. For example, duringstandard SCS treatment, the patient typically experiences a painreduction at a particular amplitude, and begins experiencing pain fromthe therapeutic signal (which may have a sudden onset, as describedabove) at from about 1.2 to about 1.6 times that amplitude. Thiscorresponds to an average dynamic range of about 1.4. In addition,patients receiving standard SCS stimulation typically wish to receivethe stimulation at close to the pain onset level because the therapy isoften most effective at that level. Accordingly, patient preferences mayfurther reduce the effective dynamic range. By contrast, therapy inaccordance with embodiments of the presently disclosed technologyresulted in patients obtaining pain relief at 1 mA or less, and notencountering pain or muscle capture until the applied signal had anamplitude of 4 mA, and in some cases up to about 5 mA, 6 mA, or 8 mA,corresponding to a much larger dynamic range (e.g., larger than 1.6 or60% in some embodiments, or larger than 100% in other embodiments). Inparticular embodiments, therapy resulted at 2-3 mA, and sensation atgreater than 7 mA. Even at the forgoing amplitude levels, the painexperienced by the patients was significantly less than that associatedwith standard SCS pain onset. An expected advantage of this result isthat the patient and practitioner can have significantly wider latitudein selecting an appropriate therapy amplitude with the presentlydisclosed methodology than with standard SCS methodologies. For example,the practitioner can increase the signal amplitude in an effort toaffect more (e.g., deeper) fibers at the spinal cord, without triggeringunwanted side effects. The existence of a wider amplitude window mayalso contribute to the relative insensitivity of the presently disclosedtherapy to changes in patient posture and/or activity. For example, ifthe relative position between the implanted lead and the target neuralpopulation changes as the patient moves, the effective strength of thesignal when it reaches the target neural population may also change.When the target neural population is insensitive to a wider range ofsignal strengths, this effect can in turn allow greater patient range ofmotion without triggering undesirable side effects.

FIG. 7A illustrates a graph 700 identifying amplitude as a function offrequency for conventional SCS and for therapy in accordance withembodiments of the presently disclosed technology. Threshold amplitudelevel 701 indicates generally the minimum amplitude necessary to achievea therapeutic effect, e.g., pain reduction. A first region 702corresponds to amplitudes, as a function of frequency, for which thepatient senses paresthesia induced by the therapy, pain induced by thetherapy, and/or uncomfortable or undesired muscle stimulation induced bythe therapy. As shown in FIG. 7A, at conventional SCS frequencies, thefirst region 702 extends below the threshold amplitude level 701.Accordingly, a second region 703 indicates that the patient undergoingconventional SCS therapy typically detects paresthesia, other sensoryeffects, and/or undesirable motor effects below the amplitude necessaryto achieve a therapeutic effect. One or more of these side effects arealso present at amplitudes above the threshold amplitude level 701required to achieve the therapeutic effect. By contrast, at frequenciesassociated with the presently disclosed technology, a “window” 704exists between the threshold amplitude level 701 and the first region702. Accordingly, the patient can receive therapeutic benefits atamplitudes above the threshold amplitude level 701, and below theamplitude at which the patient may experience undesirable side effects(e.g., paresthesia, sensory effects and/or motor effects).

FIG. 7B is a graph of amplitude as a function of frequency, illustratingrepresentative regimes in accordance with a particular model for therapydelivery. FIG. 7B illustrates a sensation/paresthesia threshold, and atherapy threshold. These curves cross, creating four regions, each ofwhich is identified in FIG. 7B based on whether or not the patientreceives therapy, and whether or not the patient perceives sensationand/or paresthesia. Particular embodiments of the presently disclosedtechnology operate in the range identified as “Therapy, NoSensation/Paresthesia” to produce the therapeutic results withoutparesthesia, discussed above.

Although the presently disclosed therapies may allow the practitioner toprovide modulation over a broader range of amplitudes, in at least somecases, the practitioner may not need to use the entire range. Forexample, as described above, the instances in which the patient may needto adjust the therapy may be significantly reduced when compared withstandard SCS therapy because the presently disclosed therapy isrelatively insensitive to patient position, posture and activity level.In addition to or in lieu of the foregoing effect, the amplitude of thesignals applied in accordance with the presently disclosed techniquesmay be lower than the amplitude associated with standard SCS because thepresently disclosed techniques may target neurons that are closer to thesurface of the spinal cord. For example, it is believed that the nervefibers associated with low back pain enter the spinal cord between T9and T12 (inclusive), and are thus close to the spinal cord surface atthese vertebral locations. Accordingly, the strength of the therapeuticsignal (e.g., the current amplitude) can be modest because the signalneed not penetrate through a significant depth of spinal cord tissue tohave the intended effect. Such low amplitude signals can have a reduced(or zero) tendency for triggering side effects, such as unwanted sensoryand/or motor responses. Such low amplitude signals can also reduce thepower required by the implanted pulse generator, and can thereforeextend the battery life and the associated time between rechargingand/or replacing the battery.

Yet another expected benefit of providing therapy in accordance with thepresently disclosed parameters is that the practitioner need not implantthe lead with the same level of precision as is typically required forstandard SCS lead placement. For example, while at least some of theforegoing results were obtained for patients having two leads (onepositioned on either side of the spinal cord midline), it is expectedthat patients will receive the same or generally similar pain reliefwith only a single lead placed at the midline. Accordingly, thepractitioner may need to implant only one lead, rather than two. It isstill further expected that the patient may receive pain relief on oneside of the body when the lead is positioned offset from the spinal cordmidline in the opposite direction. Thus, even if the patient hasbilateral pain, e.g., with pain worse on one side than the other, thepatient's pain can be addressed with a single implanted lead. Stillfurther, it is expected that the lead position can vary laterally fromthe anatomical and/or physiological spinal cord midline to a position3-5 mm. away from the spinal cord midline (e.g., out to the dorsal rootentry zone or DREZ). The foregoing identifiers of the midline maydiffer, but the expectation is that the foregoing range is effective forboth anatomical and physiological identifications of the midline, e.g.,as a result of the robust nature of the present therapy. Yet further, itis expected that the lead (or more particularly, the active contact orcontacts on the lead) can be positioned at any of a variety of axiallocations in a range of about T8-T11 or T8-T12 in one embodiment, and arange of one to two vertebral bodies within T8-T11 or T8-T12 in anotherembodiment, while still providing effective treatment for low back pain.Accordingly, the practitioner's selected implant site need not beidentified or located as precisely as it is for standard SCS procedures(axially and/or laterally), while still producing significant patientbenefits. In particular, the practitioner can locate the active contactswithin the foregoing ranges without adjusting the contact positions inan effort to increase treatment efficacy and/or patient comfort. Inaddition, in particular embodiments, contacts at the foregoing locationscan be the only active contacts delivering therapy to the patient. Theforegoing features, alone or in combination, can reduce the amount oftime required to implant the lead, and can give the practitioner greaterflexibility when implanting the lead. For example, if the patient hasscar tissue or another impediment at a preferred implant site, thepractitioner can locate the lead elsewhere and still obtain beneficialresults.

Still another expected benefit, which can result from the foregoingobserved insensitivities to lead placement and signal amplitude, is thatthe need for conducting a mapping procedure at the time the lead isimplanted may be significantly reduced or eliminated. This is anadvantage for both the patient and the practitioner because it reducesthe amount of time and effort required to establish an effective therapyregimen. In particular, standard SCS therapy typically requires that thepractitioner adjust the position of the lead and the amplitude of thesignals delivered by the lead, while the patient is in the operatingroom reporting whether or not pain reduction is achieved. Because thepresently disclosed techniques are relatively insensitive to leadposition and amplitude, the mapping process can be eliminated entirely.Instead, the practitioner can place the lead at a selected vertebrallocation (e.g., about T8-T11) and apply the signal at a pre-selectedamplitude (e.g., 2 to 3 mA), with a significantly reduced or eliminatedtrial-and-error optimization process (for a contact selection and/oramplitude selection), and then release the patient. In addition to or inlieu of the foregoing effect, the practitioner can, in at least someembodiments, provide effective therapy to the patient with a simplebipole arrangement of electrodes, as opposed to a tripole or other morecomplex arrangement that is used in existing systems to steer orotherwise direct therapeutic signals. In light of the foregoingeffect(s), it is expected that the time required to complete a patientlead implant procedure and select signal delivery parameters can bereduced by a factor of two or more, in particular embodiments. As aresult, the practitioner can treat more patients per day, and thepatients can more quickly engage in activities without pain.

The foregoing effect(s) can extend not only to the mapping procedureconducted at the practitioner's facility, but also to the subsequenttrial period. In particular, patients receiving standard SCS treatmenttypically spend a week after receiving a lead implant during which theyadjust the amplitude applied to the lead in an attempt to establishsuitable amplitudes for any of a variety of patient positions andpatient activities. Because embodiments of the presently disclosedtherapy are relatively insensitive to patient position and activitylevel, the need for this trial and error period can be reduced oreliminated.

Still another expected benefit associated with embodiments of thepresently disclosed treatment is that the treatment may be lesssusceptible to patient habituation. In particular, it is expected thatin at least some cases, the high frequency signal applied to the patientcan produce an asynchronous neural response, as is disclosed inco-pending U.S. application Ser. No. 12/362,244, incorporated herein byreference. The asynchronous response may be less likely to producehabituation than a synchronous response, which can result from lowerfrequency modulation.

Yet another feature of embodiments of the foregoing therapy is that thetherapy can be applied without distinguishing between anodic contactsand cathodic contacts. As described in greater detail in U.S.application Ser. No. 12/765,790, incorporated herein by reference, thisfeature can simplify the process of establishing a therapy regimen forthe patient. In addition, due to the high frequency of the waveform, theadjacent tissue may perceive the waveform as a pseudo steady statesignal. As a result of either or both of the foregoing effects, tissueadjacent both electrodes may be beneficially affected. This is unlikestandard SCS waveforms for which one electrode is consistently cathodicand another is consistently anodic.

In any of the foregoing embodiments, aspects of the therapy provided tothe patient may be varied, while still obtaining beneficial results. Forexample, the location of the lead body (and in particular, the lead bodyelectrodes or contacts) can be varied over the significant lateraland/or axial ranges described above. Other characteristics of theapplied signal can also be varied. For example, the signal can bedelivered at a frequency of from about 1.5 kHz to about 100 kHz, and inparticular embodiments, from about 1.5 kHz to about 50 kHz. In moreparticular embodiments, the signal can be provided at frequencies offrom about 3 kHz to about 20 kHz, or from about 3 kHz to about 15 kHz,or from about 5 kHz to about 15 kHz, or from about 3 kHz to about 10kHz. The amplitude of the signal can range from about 0.1 mA to about 20mA in a particular embodiment, and in further particular embodiments,can range from about 0.5 mA to about 10 mA, or about 0.5 mA to about 4mA, or about 0.5 mA to about 2.5 mA. The amplitude of the applied signalcan be ramped up and/or down. In particular embodiments, the amplitudecan be increased or set at an initial level to establish a therapeuticeffect, and then reduced to a lower level to save power withoutforsaking efficacy, as is disclosed in pending U.S. application Ser. No.12/264,836, filed Nov. 4, 2008, incorporated herein by reference. Inparticular embodiments, the signal amplitude refers to the electricalcurrent level, e.g., for current-controlled systems. In otherembodiments, the signal amplitude can refer to the electrical voltagelevel, e.g., for voltage-controlled systems. The pulse width (e.g., forjust the cathodic phase of the pulses) can vary from about 10microseconds to about 333 microseconds. In further particularembodiments, the pulse width can range from about 25 microseconds toabout 166 microseconds, or from about 33 microseconds to about 100microseconds, or from about 50 microseconds to about 166 microseconds,or from about 30 to about 35 microseconds. The specific values selectedfor the foregoing parameters may vary from patient to patient and/orfrom indication to indication and/or on the basis of the selectedvertebral location. In addition, the methodology may make use of otherparameters, in addition to or in lieu of those described above, tomonitor and/or control patient therapy. For example, in cases for whichthe pulse generator includes a constant voltage arrangement rather thana constant current arrangement, the current values described above maybe replaced with corresponding voltage values.

In at least some embodiments, it is expected that the foregoingamplitudes will be suprathreshold. As used herein, the term“suprathreshold” refers generally to a signal that produces, triggersand/or otherwise results in an action potential at the target neuron(s)or neural population. It is also expected that, in at least someembodiments, the neural response to the foregoing signals will beasynchronous, as described above. Accordingly, the frequency of thesignal can be selected to be higher (e.g., between two and ten timeshigher) than the refractory period of the target neurons at thepatient's spinal cord, which in at least some embodiments is expected toproduce an asynchronous response.

Patients can receive multiple signals in accordance with still furtherembodiments of the disclosure. For example, patients can receive two ormore signals, each with different signal delivery parameters. In oneparticular example, the signals are interleaved with each other. Forinstance, the patient can receive 5 kHz pulses interleaved with 10 kHzpulses. In other embodiments, patients can receive sequential “packets”of pulses at different frequencies, with each packet having a durationof less than one second, several seconds, several minutes, or longerdepending upon the particular patient and indication.

4.0 Effects of High Frequency Modulation on the Autonomic Nervous System

The autonomic nervous system (ANS) is largely responsible forautomatically and subconsciously regulating many systems of the body,including the cardiovascular, renal, gastrointestinal, andthermoregulatory systems. By regulating these systems, the ANS canenable the body to adapt to changes in the environment, for example,changing states of stress. Autonomic nerve fibers innervate a variety oftissues, including cardiac muscle, smooth muscle, and glands. Thesenerve fibers help to regulate functions associated with the foregoingtissues, including but not limited to blood pressure, blood flow,gastrointestinal functions, body temperature, bronchial dilation, bloodglucose levels, metabolism, micturition and defecation, pupilary lightand accommodation reflexes, and glandular secretions. The effect of theANS on selected organs can be demonstrated by cutting the nerve fibers.If the autonomic nerve fibers to an organ are cut or otherwiseinterrupted, the organ will fail to adjust to changing conditions. Forexample, if the autonomic nerve fibers to the heart are cut, the heartwill largely lose its ability to increase cardiac output under stress.

The autonomic nervous system includes the sympathetic system and theparasympathetic system. These two systems in many instances haveopposite effects and accordingly, each one can balance the effect of theother. FIG. 8 illustrates representative organs innervated by the ANS,together with the effects created by both the sympathetic system and theparasympathetic system.

In accordance with the presently disclosed technology, it is believedthat organ dysfunction may be caused by (a) an imbalance in theparasympathetic and sympathetic effects, and/or (b) the combined effectof the parasympathetic and sympathetic systems being higher or lowerthan normal. The foregoing effects individually or together, arereferred to herein generally as autonomic system deficits. One approachto addressing organ dysfunction in accordance with embodiments of thepresent technology is to apply high frequency signals to normalize theautonomic nervous system, e.g., to reduce or eliminate autonomic systemdeficits. Accordingly, normalizing the autonomic nervous system caninclude providing or increasing the level of homeostatis or equilibriumof the ANS system, and/or altering the overall output of the ANS. Forexample, the autonomic system can experience a deficit when the effectof the sympathetic system is stronger than or dominates the effect ofthe parasympathetic system, or vice versa. Without being bound bytheory, it is believed that the high frequency modulation signals canbring equilibrium to the ANS (or at least reduce dis-equilibrium whenone of the sympathetic and parasympathetic systems is more active and/orcreates a greater effect than the other.

As was discussed above in the context of pain treatment, one possiblemechanism of action by which high frequency signals are expected toaddress pain is to reduce the excitability of wide dynamic range (WDR)neurons. It is believed that high frequency signals can operate in asimilar and/or analogous manner to reduce excitability of an overactivesympathetic or parasympathetic system and/or otherwise reduce autonomicsystem deficits.

Electrical signals to address autonomic system deficits can be appliedto the spinal cord in manners generally similar to those discussed abovein the context of reducing pain, and in accordance with modulationparameters generally similar to those described above in the context ofreducing pain. For example, the signal can be applied in accordance withany of the foregoing frequency ranges of from about 1.5 kHz to about 100kHz, and in accordance with any of the foregoing current amplituderanges of from about 0.1 mA to about 20 mA. Depending upon theembodiment, a particular modulation signal can be directed to (a) reducepain, (b) control the autonomic system (e.g., reduce autonomic systemdeficits) or (c) both.

In at least some embodiments, the modulation signal can be applied at aparticular vertebral level associated with the organ of interest. Forexample, the modulation signal can be applied to upper thoracicvertebral levels to address cardiac and/or pulmonary autonomic systemdeficits. In other embodiments, the modulation signal can be applied tocervical levels of the spinal cord (e.g., C3-C5) to address organsassociated not only with that vertebral level, but also with vertebrallevels below it. Further details of particular vertebral levels andassociated organs are described in U.S. Pat. No. 8,170,675, previouslyincorporated herein by reference.

The high frequency modulation signal can operate on the targeted organor organs in accordance with any of a number of mechanisms. For example,the high frequency modulation signal can have an effect on a network ofneurons, rather than an effect on a particular neuron. This networkeffect can in turn operate to normalize the autonomic system describedabove. In accordance with another mechanism of action, the highfrequency modulation signal can affect gene expression. For example, thehigh frequency modulation signal can cause genes which otherwise are notexpressed, or are inadequately expressed, to express or increaseexpression. In another example, gene expression associated with aparticular abnormality can be down-regulated by the high frequencymodulation signal.

Either or both of the foregoing mechanisms of action can have acascading effect on other systems. For example, the effect of increasinggene expression and/or the network effect can be to increase metabolism,which in turn can increase hormone production, which in turn can affectthe target organ. It is believed that, as a result of this indirecteffect, the ultimate effect on the organ may not occur instantaneously,but rather may take time (e.g., days) to develop, in response to amodulation signal that is applied to the patient for over a similarperiod of time (e.g., days).

The effect of the high frequency modulation signal on the autonomicsystem can operate to decrease incontinence, improve digestion, reversethe effects of heart conditions that produce low cardiac output,normalize a patient's diabetic response, and/or reduce impotence, amongother effects. In any of these or other embodiments, the effect may notbe limited to increasing organ output or decreasing organ output, butmay instead produce a normalized organ output, which may includeincreasing or decreasing output depending upon the initial state of theorgan.

In at least some embodiments, a practitioner can obtain feedback fromthe patient to detect the effect of the high frequency modulation signalon the ANS, and, if necessary or desired, modify the signal deliveryparameters to improve the effect. For example, the practitioner and/orthe patient can directly observe/report changes in heart condition,diabetic response, pulmonary function, sexual function, and/or otherfunctions. In other embodiments, the physician can more directly monitorand distinguish between effects on the sympathetic system and/or theparasympathetic system. Suitable products for monitoring these systemsinclude those available from the Ansar Group, Inc. of Philadelphia, Pa.

In at least some embodiments, the patient's ANS response to highfrequency modulation signals may be correlated with the patient's painresponse to such signals. Accordingly, detecting the patient's ANSresponse in accordance with any of the foregoing techniques can producea supplemental or surrogate indication of the patient's pain response.This in turn can provide an alternate and in some cases more objectiveindication of the patient's pain response and/or response to othertreatments for other ANS deficits.

5.0 Representative Examples

Embodiments of the presently disclosed technology are described in thefollowing representative examples. A method for treating a patient inaccordance with one example includes reducing or eliminating anautonomic system deficit of the patient by applying or directingapplication of an electrical signal to a spinal cord or spinal cordregion of the patient, with the electrical signal having a frequency ina range of from about 1.5 kHz to about 100 kHz. In a further particularaspect of this example, reducing or eliminating the autonomic systemdeficit includes reducing or eliminating an imbalance between an effectof the patient's sympathetic system and an effect of the patient'sparasympathetic system. In another aspect of this example, reducing oreliminating the autonomic system deficit includes normalizing a combinedeffect of the patient's sympathetic and parasympathetic systems. Instill a further aspect, applying or directing application of theelectrical signal includes applying or directing application of thesignal to WDR neurons of the patient's spinal cord. In any of theseexamples, the autonomic system deficit can affect any of a number ofrepresentative target organs, including target organs of the patient'scardiovascular system and/or the patient's gastrointestinal system.

A method for treating a patient in accordance with anotherrepresentative example includes implanting a signal delivery device at alocation (e.g., an epidural location) proximate to the patient's spinalcord, based at least in part on an indication that the patient has anautonomic system deficit. The method can further include directing anelectrical signal to the patient's spinal cord at a frequency in a rangeof from about 1.5 kHz to about 100 kHz (e.g., from about 3 kHz to about20 kHz) to reduce or eliminate the autonomic system deficit. Reducing oreliminating the autonomic system deficit can include reducing oreliminating an imbalance between an effect of the patient's sympatheticsystem and an effect of the patient's parasympathetic system, and/ornormalizing a combined effect of the patient's sympathetic andparasympathetic system. The electrical signal can be directed to WDRneurons of the patient's spinal cord and/or the dorsal horn of thepatient's spinal cord. In further embodiments, the method can includemonitoring the patient's autonomic system function, e.g., by observing afunction of the patient controlled by the autonomic system and/ormonitoring the patient with a medical device. In response to resultsobtained from monitoring the patient's autonomic system function, themethod can further include adjusting at least one signal deliveryparameter in accordance with which the electrical signal is applied tothe patient's spinal cord.

Still a further representative example of a method in accordance withthe present technology includes directing an electrical therapy signalto a patient's spinal cord to reduce or inhibit pain in the patient,with the electrical therapy signal having a frequency of from about 1.5kHz to about 100 kHz. The method can further include receiving feedbackcorresponding to an autonomic system response by the patient to theelectrical therapy signal, and, based at least in part on the feedback,identifying a characteristic of the patient's pain response to theelectrical therapy signal. In particular embodiments, the electricaltherapy signal is delivered without the electrical therapy signalcausing paresthesia in the patient. In further particular embodiments,the method can include adjusting at least one signal delivery parameterin accordance with which the electrical therapy signal is directed tothe patient's spinal cord, e.g., based at least in part on the feedbackreceived from the patient.

The methods disclosed herein include and encompass, in addition tomethods of making and using the disclosed devices and systems, methodsof instructing others to make and use the disclosed devices and systems.For example, a method in accordance with a particular embodimentincludes reducing or eliminating an autonomic system deficit of thepatient by applying an electrical signal to a spinal cord of thepatient, with the electrical signal having a frequency in a range offrom about 1.5 kHz to about 100 kHz. A method in accordance with anotherembodiment includes instructing or directing such a method. Accordingly,any and all methods of use and manufacture disclosed herein also fullydisclose and enable corresponding methods of instructing such methods ofuse and manufacture.

In still further examples, some or all of the foregoing methodoperations can be performed automatically by computer-based systems.Accordingly, embodiments of the present technology includecomputer-readable media and/or other non-transitory system componentsthat are programmed or otherwise configured to perform such operations.

In still a further examples, there are provided methods for treating apatient's organ dysfunction resulting from an autonomic system deficit.The methods include applying a therapeutic signal to the patient'sspinal cord so as to modulate (a) a sympathetic stimulation effect, (b)a parasympathetic effect, or (c) both a sympathetic effect and aparasympathetic effect on the target organ. Examples of target organsand corresponding sympathetic and parasympathetic effects are listed inFIG. 8. For example, methods are provided for treating a heart conditionof the SA node, atria, AV node, Purkinje system, or ventricles by theapplication of a neuromodulation signal to the patient's spinal cord. Atleast a portion of the neuromodulation signal may have a frequencybetween about 1.5 kHz and 100 kHz, and may be applied at an amplitudesuch that the patient does not perceive paresthesia or any otheruncomfortable stimulation sensations (i.e., the therapy signal does notgenerate paresthesia). Detailed examples of therapeutic signalparameters are provided above. The neuromodulation signal can thusmodulate (a) a sympathetic stimulation effect, (b) a parasympatheticeffect, or (c) both a sympathetic effect and a parasympathetic effect onthe heart.

From the foregoing, it will be appreciated that specific embodiments ofthe technology have been described herein for purposes of illustration,but that various modifications may be made without deviating from thepresent disclosure. For example, therapies described in the context ofparticular vertebral locations to treat low back pain may be applied toother vertebral levels to treat other types of pain. In still furtherembodiments, the therapeutic effect can include indications in additionto or in lieu of pain. Methods and systems in accordance with particularembodiments of the present technology control autonomic system deficitsvia high frequency signals applied to the spinal cord, e.g., the WDRneurons and/or other dorsally located neural structures. In otherembodiments, the signals can be applied to other neural populations,e.g., the dorsal root ganglia and/or peripheral nerves. Certain aspectsof the disclosure described in the context of particular embodiments maybe combined or eliminated in other embodiments. For example, patientscan receive treatment at multiple vertebral levels and/or via leads orother signal delivery devices positioned at multiple locations. Theforegoing mechanisms of action are believed to account for the patientresponses observed during treatment in accordance with the presentlydisclosed technology; however, other mechanisms or processes may operatein addition to or in lieu of the foregoing mechanisms in at least someinstances. Further, while advantages associated with certain embodimentshave been described in the context of those embodiments, otherembodiments may also exhibit such advantages, and not all embodimentsneed necessarily exhibit such advantages to fall within the scope of thepresent technology. Accordingly, the present disclosure and associatedtechnology can encompass other embodiments not expressly shown ordescribed herein.

I claim:
 1. A method for treating a patient, comprising: reducing ormodifying an organ dysfunction of an identified organ in the patient byapplying or directing application of an electrical signal to WDR neuronsof the patient's spinal cord via an implanted signal delivery device, ata vertebral level corresponding to the identified organ, the electricalsignal having a frequency of from about 1.5 kHz to about 100 kHz.
 2. Themethod of claim 1 wherein reducing or modifying the organ dysfunctionincludes reducing or modifying an imbalance between an effect of thepatient's sympathetic system and an effect of the patient'sparasympathetic system.
 3. The method of claim 1 wherein reducing ormodifying the organ dysfunction includes normalizing a combined effectof the patient's sympathetic and parasympathetic systems.
 4. The methodof claim 1 wherein the electrical signal has a frequency in a range offrom about 3 kHz to about 20 kHz.
 5. The method of claim 1 wherein theelectrical signal is directed to the patient's dorsal horn.
 6. A methodfor evaluating a patient's pain, comprising: directing an electricaltherapy signal via an implanted signal delivery device to reduce orinhibit pain in the patient, the electrical therapy signal having afrequency of from about 1.5 kHz to about 100 kHz; receiving feedbackcorresponding to an autonomic system response of the patient to theelectrical therapy signal, wherein the autonomic system response is areduction or modification of an organ dysfunction achieved bynormalizing a combined effect of the patient's sympathetic andparasympathetic systems; and based at least in part on the feedback,identifying a characteristic of a pain response of the patient to theelectrical therapy signal.
 7. The method of claim 6, further comprisingadjusting at least one signal delivery parameter in accordance withwhich the electrical therapy signal is directed to the patient's spinalcord, based at least in part on the feedback.
 8. The method of claim 7wherein adjusting at least one signal delivery parameter improves aneffect of the electrical therapy signal.
 9. The method of claim 6wherein receiving feedback includes directly observing changes in thecharacteristic of the patient's pain response.
 10. The method of claim 9wherein the autonomic system response is a heart condition, a diabeticresponse, a pulmonary function, or a sexual function.
 11. The method ofclaim 6 wherein receiving feedback includes directly observing afunction of the patient controlled by the autonomic nervous system. 12.The method of claim 6 wherein receiving feedback includes directlyobserving a function of the patient controlled by an organ identified ashaving the organ dysfunction.
 13. The method of claim 6, furthercomprising correlating the patient's autonomic system response to theelectrical therapy signal with the characteristic of the patient's painresponse.
 14. The method of claim 13 wherein the patient's autonomicsystem response to the electrical therapy signal indicates the patient'spain response.
 15. The method of claim 6 wherein directing applicationof the electrical signal includes directing application of theelectrical signal to WDR neurons of the patient's spinal cord.
 16. Themethod of claim 6 wherein directing application of the electrical signalincludes directing application of the electrical signal at a vertebrallevel corresponding to an organ having the organ dysfunction.
 17. Themethod of claim 16 wherein the vertebral level of the patient's spinalcord is an upper thoracic vertebral level.
 18. The method of claim 16wherein the vertebral level of the patient's spinal cord is a cervicallevel of the spinal cord.
 19. The method of claim 6 wherein theautonomic system response affects a target organ of the patient'scardiovascular system.
 20. The method of claim 6 wherein the autonomicsystem response affects a target organ of the patient's gastrointestinalsystem.
 21. The method of claim 6 wherein directing the electricaltherapy signal includes directing the electrical therapy signal withoutthe electrical therapy signal causing paresthesia in the patient. 22.The method of claim 6 wherein receiving feedback includes monitoring thepatient's autonomic system with a medical device.
 23. A method forevaluating a patient's pain, comprising: directing an electrical therapysignal to the patient's spinal cord via an implanted signal deliverydevice to reduce or inhibit pain in the patient, the electrical therapysignal having a frequency of from about 1.5 kHz to about 100 kHz;receiving feedback corresponding to the patient's autonomic systemresponse to the electrical therapy signal by monitoring an input from asensor with a control algorithm embedded within the implanted signaldelivery device; and based at least in part on the feedback, identifyinga characteristic of the patient's pain response to the electricaltherapy signal.
 24. The method of claim 23 wherein the sensor is anaccelerometer, a gyroscope, a blood pressure sensor, an impedancesensor, a thoracic impedance sensor, a heart rate monitor, a respirationrate monitor, or a temperature sensor.
 25. The method of claim 23,further comprising; initializing the sensor with a value; setting adelta change threshold for the sensor; and setting a confidence intervalfor the control algorithm.
 26. The method of claim 25, furthercomprising determining a value range based on the confidence interval ofthe control algorithm.
 27. The method of claim 25 wherein the deltachange threshold indicates if the sensor input is outside of an expectedsensor input range.
 28. The method of claim 27, further comprisingprogramming the implanted signal delivery device to, monitor the sensorinput and, if the monitored sensor input is outside of the expectedsensor input range, change a stimulation program or a stimulationparameter.
 29. The method of claim 28 wherein the implanted signaldelivery device emits an alert if the implanted signal delivery devicechanged the stimulation program or the stimulation parameter.